JC virus (JCV), a ubiquitous small DNA virus of the polyomavirus genus, is the agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV circulates widely in the population, apparently following urinary excretion, although paradoxically, the virus remains strongly population associated. PML is the cause of death in approximately 5% of AIDS patients in the USA. Most recently, our efforts in this project have been directed at characterizing the natural variation in the DNA sequence that occurs in both the regulatory region and the coding region of the viral genome, and determining the significance of these rearrangements for both the biology of the virus, and the pathogenesis of the CNS disease. The regulatory region of virus excreted from the urinary tract is quite stable when circulating in the population, but rearranges extensively by unknown mechanisms before it attacks the brain of immunocompromised individuals. These brain adapted variants are each unique in their regulatory regions, and fortunately, appear not to be more readily transmissible from the urine. The concern is that with more PML present in the population, brain adapted virus which also has a selective advantage in the kidney might begin to circulate in the population, putting infected individuals at higher risk of brain disease. In addition to understanding the risk to infected individuals, we wish to explain the 10-fold difference in the prevalence of PML in AIDS patients which ranges from as high as 10% in some series in Europe to near 1% in Africa and Brazil. The work on JC virus has been instructive in understanding the peculiar virulence of some strains of another human polyomavirus, BK virus. Rather than the brain, BKV ordinarily infects the kidney progressively, both in AIDS patients and in immunosuppressed renal allograft recipients. Previous work in collaboration with the group at the University of Cincinnati has shown that BK virus associated with end-stage renal disease (ESRD) is rearranged in the regulatory region similarly to JCV in the brain. Furthermore, these pathogenic strains can have coding region mutations in the regulatory early protein, T-antigen, which are thought alter DNA-binding activity. Rarely, BKV also invades the brain in immunocompromised patients, and we are following up such individuals to characterize the pathogenic virus and the changes occurring during CNS infection. Preliminary evidence suggests the changes in BKV from the kidney are analogous to those occurring in JCV in the PML brain. The features of each of these viruses will help us to understand the pathogenesis of the other. - JC virus, BK virus, polyomavirus, progressive multifocal leukoencephalopathy, AIDS, CNS, brain, kidney, urine, CNS